Influence of the APOE genotypes in some atherosclerotic risk factors

The aim of this work was to study the distribution of apolipoprotein E (APOE) genotypes and their association with some atherosclerotic risk factors, all of them modifiable: total, HDL and LDL cholesterol, triglycerides, systolic and diastolic blood pressure, BMI, waist circumference and smoking. The sample population was constituted of 672 healthy subjects recruited in the Lisbon area. Lipids were quantified by usual automatic enzymatic methods and the APOE genotypes performed in accordance with Hixson and Vernier. Blood pressure measurement and hypertension classification followed international specifications. The frequency distribution of APOE alleles was: epsilon2 = 6.4%, epsilon3 = 83.6% and epsilon4 = 10.0% and the more prevalent genotypes were epsilon2/epsilon3, epsilon3/epsilon3 and epsilon3/epsilon4 respectively 11.0%, 70.1% and 16.1%. We could only observe associations among the most prevalent genotypes and lipids, always statistically significant, specially when the epsilon4 allele was present which was even proved by an higher prevalence of epsilon4 in dyslipidemic subjects with the only exception of those with low HDL-c values. A stronger intervention in the epsilon4 carriers is so recommended through appropriate intervention measures on the connected modifiable risk factors

CP-odd and CP-even Weak-Basis Invariants in the Presence of Vector-Like Quarks

We propose a minimal set of weak-basis invariants in an extension of the SM where one up-type isosinglet vector-like quark is introduced, which allows us to obtain all the physical content of the CKM matrix. We present CP-odd invariants of lower order in mass than the one in the SM, which may have important consequences for Baryogenesis. We study the extreme chiral limit, where the two lightest generations have vanishing mass, showing that in this extension, contrary to the SM, CP violation can be observed in collisions much above the electroweak scale.Comment: 18 page

Synaptic mechanisms for associative learning in the cerebellar nuclei

Associative learning during delay eyeblink conditioning (EBC) depends on an intact cerebellum. However, the relative contribution of changes in the cerebellar nuclei to learning remains a subject of ongoing debate. In particular, little is known about the changes in synaptic inputs to cerebellar nuclei neurons that take place during EBC and how they shape the membrane potential of these neurons. Here, we probed the ability of these inputs to support associative learning in mice, and investigated structural and cell-physiological changes within the cerebellar nuclei during learning. We find that optogenetic stimulation of mossy fiber afferents to the anterior interposed nucleus (AIP) can substitute for a conditioned stimulus and is sufficient to elicit conditioned responses (CRs) that are adaptively well-timed. Further, EBC induces structural changes in mossy fiber and inhibitory inputs, but not in climbing fiber inputs, and it leads to changes in subthreshold processing of AIP neurons that correlate with conditioned eyelid movements. The changes in synaptic and spiking activity that precede the CRs allow for a decoder to distinguish trials with a CR. Our data reveal how structural and physiological modifications of synaptic inputs to cerebellar nuclei neurons can facilitate learning.</p

Synaptic mechanisms for associative learning in the cerebellar nuclei

Associative learning during delay eyeblink conditioning (EBC) depends on an intact cerebellum. However, the relative contribution of changes in the cerebellar nuclei to learning remains a subject of ongoing debate. In particular, little is known about the changes in synaptic inputs to cerebellar nuclei neurons that take place during EBC and how they shape the membrane potential of these neurons. Here, we probed the ability of these inputs to support associative learning in mice, and investigated structural and cell-physiological changes within the cerebellar nuclei during learning. We find that optogenetic stimulation of mossy fiber afferents to the anterior interposed nucleus (AIP) can substitute for a conditioned stimulus and is sufficient to elicit conditioned responses (CRs) that are adaptively well-timed. Further, EBC induces structural changes in mossy fiber and inhibitory inputs, but not in climbing fiber inputs, and it leads to changes in subthreshold processing of AIP neurons that correlate with conditioned eyelid movements. The changes in synaptic and spiking activity that precede the CRs allow for a decoder to distinguish trials with a CR. Our data reveal how structural and physiological modifications of synaptic inputs to cerebellar nuclei neurons can facilitate learning.</p

APOE genotypes and dyslipidemias in a sample of the Portuguese population

The objective of this work was to study the distribution of apolipoprotein E (APOE) genotypes in a sample of the Portuguese population, and its association with the dyslipidemias observed. Study participants were healthy users of local Public Health Laboratories in six regions of mainland Portugal (Porto, Vila Real, Viseu, Lisboa, Portalegre and Faro). A total of 779 men and 1153 women aged 15-74 years agreed to participate. Fasting lipid levels and APOE genotypes were determined centrally at the National Institute of Health in Lisboa. The frequency distribution of APOE alleles was: epsilon2=5.3%, epsilon3=84.9% and epsilon4=9.8%. Dyslipidemias were present in 66.6% of men and 60.7% of women. Comparison of APOE genotypes and relative allele frequencies showed that in dyslipidemic compared to normolipidemic subjects, the epsilon4 allele was more frequent in both sexes, although in a more pronounced way in men than in women due to higher frequencies of epsilon3/epsilon4 and epsilon4/epsilon4 genotypes. The known association of the epsilon4 allele with high cholesterol levels, the association of the epsilon2 allele with low cholesterol levels, and the association of the epsilon2 allele with high levels of triglycerides and low levels of high-density lipoprotein-cholesterol were confirmed in this study

A genome-wide association study using a DNA pooling strategy identifies BBS9 and GLIS3 as novel loci influencing patient’s outcome after stroke

Stroke is a major cause of morbidity in developed countries and therefore finding adequate treatments to promote patient’s recovery is a priority task, requiring the elucidation of the molecular pathways influencing brain recovery. Few studies, however, have assessed the role of genes in stroke outcome. This study describes a pilot genome-wide association study (GWAS) to identify genetic factors contributing to patient’s outcome, using a DNA pooling design. Methods: Patient’s outcome was assessed using the modified Rankin Scale (mRS) three months after stroke. Using the 250K Affymetrix GeneChip Mapping Assay® – Nsp I, we compared SNP allele frequencies in a pool of non-disabled stroke patients (N=87, mRS=0), with a pool of severely disabled or deceased patients (N=100, mRS>=3). The 100 most interesting SNPs were selected for validation by individual genotyping. Results: 36 SNPs were validated, showing significant differences between patients with extremely good and extremely poor outcome at three months (1.7x10-4 ).This work was supported by the grant PTDC/SAU-GMG/64426/2006, Fundação para a Ciência e Tecnologia (FCT). Helena Manso and Tiago Krug were supported by FCT fellowships

Mitochondrial haplogroup H1 is protective for ischemic stroke in Portuguese patient

BACKGROUND: The genetic contribution to stroke is well established but it has proven difficult to identify the genes and the disease-associated alleles mediating this effect, possibly because only nuclear genes have been intensely investigated so far. Mitochondrial DNA (mtDNA) has been implicated in several disorders having stroke as one of its clinical manifestations. The aim of this case-control study was to assess the contribution of mtDNA polymorphisms and haplogroups to ischemic stroke risk. METHODS: We genotyped 19 mtDNA single nucleotide polymorphisms (SNPs) defining the major European haplogroups in 534 ischemic stroke patients and 499 controls collected in Portugal, and tested their allelic and haplogroup association with ischemic stroke risk. RESULTS: Haplogroup H1 was found to be significantly less frequent in stroke patients than in controls (OR = 0.61, 95% CI = 0.45-0.83, p = 0.001), when comparing each clade against all other haplogroups pooled together. Conversely, the pre-HV/HV and U mtDNA lineages emerge as potential genetic factors conferring risk for stroke (OR = 3.14, 95% CI = 1.41-7.01, p = 0.003, and OR = 2.87, 95% CI = 1.13-7.28, p = 0.021, respectively). SNPs m.3010G>A, m.7028C>T and m.11719G>A strongly influence ischemic stroke risk, their allelic state in haplogroup H1 corroborating its protective effect. CONCLUSION: Our data suggests that mitochondrial haplogroup H1 has an impact on ischemic stroke risk in a Portuguese sample

Kalirin: a novel genetic risk factor for ischemic stroke

Cerebrovascular and cardiovascular diseases are the leading causes of death and disability worldwide. They are complex disorders resulting from the interplay of genetic and environmental factors, and may share several susceptibility genes. Several recent studies have implicated variants of the Kalirin (KALRN) gene with susceptibility to cardiovascular and metabolic phenotypes, but no studies have yet been performed in stroke patients. KALRN is involved, among others, in the inhibition of inducible nitric oxide synthase, in the regulation of ischemic signal transduction, and in neuronal morphogenesis, plasticity, and stability. The goal of the present study was to determine whether SNPs in the KALRN region on 3q13, which includes the Ropporin gene (ROPN1), predispose to ischemic stroke (IS) in a cohort of Portuguese patients and controls. We genotyped 34 tagging SNPs in the KALRN and ROPN1 chromosomal region on 565 IS patients and 517 unrelated controls, and performed genotype imputation for 405 markers on chromosome 3. We tested the single-marker association of these SNPs with IS. One SNP (rs4499545) in the ROPN1-KALRN intergenic region and two SNPs in KALRN (rs17286604 and rs11712619) showed significant (P < 0.05) allelic and genotypic (unadjusted and adjusted for hypertension, diabetes, and ever smoking) association with IS risk. Thirty-two imputed SNPs also showed an association at P < 0.05, and actual genotyping of three of these polymorphisms (rs7620580, rs6438833, and rs11712039) validated their association. Furthermore, rs11712039 was associated with IS (0.001 < P < 0.01) in a recent well-powered genomewide association study (Ikram et al. 2009). These studies suggest that variants in the KALRN gene region constitute risk factors for stroke and that KALRN may represent a common risk factor for vascular diseases

Lymphatic vessel density and VEGF-C expression are significantly different among benign and malignant thyroid lesions

Thyroid cancer is the most frequent endocrine neoplasia worldwide. The route for metastasis and loco-regional invasion preferentially occurs by lymphatic vessels. For this reason, the assessment of lymphatic vessel density (LVD) is supposed to represent both a prognostic parameter and also a potential therapeutic target. In order to evaluate the value of LVD in benign and malignant thyroid lesions, we analyzed 110 thyroidectomy specimens using D2-40, a specific marker for lymphatic vessels and vascular endothelial growth factor C (VEGF-C), the most potent molecule of lymphatic proliferation. LVD was significantly different between papillary and follicular carcinomas in total (p = 0.045) and peritumoral area (p = 0.042). Follicular adenoma and follicular carcinoma showed an important difference of intra- (p = 0.019) and peritumoral (p = 0.033) LVD. VEGF-C was more markedly expressed in malignancies than in benign lesions (p = 0.0001). Almost all cancers with high positive VEGF-C expression also exhibited increased peritumoral LVD (p = 0.049) when compared with the benign lesions. Indeed, the high peritumoral LVD of malignant thyroid lesions is an important finding for surgery planning and supports the practice of total thyroidectomy in malignant thyroid neoplasm's since the lymphatic peritumoral vessels definitely are an escape path for tumor cells

Characterisation of male breast cancer: a descriptive biomarker study from a large patient series

Male breast cancer (MBC) is rare. We assembled 446 MBCs on tissue microarrays and assessed clinicopathological information, together with data from 15 published studies, totalling 1984 cases. By immunohistochemistry we investigated 14 biomarkers (ERα, ERβ1, ERβ2, ERβ5, PR, AR, Bcl-2, HER2, p53, E-cadherin, Ki67, survivin, prolactin, FOXA1) for survival impact. The main histological subtype in our cohort and combined analyses was ductal (81%, 83%), grade 2; (40%, 44%), respectively. Cases were predominantly ERα (84%, 82%) and PR positive (74%, 71%), respectively, with HER2 expression being infrequent (2%, 10%), respectively. In our cohort, advanced age (>67) was the strongest predictor of overall (OS) and disease free survival (DFS) (p = 0.00001; p = 0.01, respectively). Node positivity negatively impacted DFS (p = 0.04). FOXA1 p = 0.005) and AR p = 0.009) were both positively prognostic for DFS, remaining upon multivariate analysis. Network analysis showed ERα, AR and FOXA1 significantly correlated. In summary, the principle phenotype of MBC was luminal A, ductal, grade 2. In ERα+ MBC, only AR had prognostic significance, suggesting AR blockade could be employed therapeutically